Literature Review on Neuropsychiatric Lupus

*Gerald B. Natanauan*

### **Abstract**

Neuropsychiatric systemic lupus erythematosus (NPSLE) had been described in several medical literatures These included the pathogenesis, mechanisms and current approach to management and treatment. Although still limited, more information is coming with the advancement of medical knowledge and technology regarding systemic lupus erythematosus and neuropsychiatric involvement. NPSLE remains elusive in the context of outright diagnosis and management. Its manifestations need to be carefully assessed before a final diagnosis is made for the proper treatment. Thus, attribution models were later developed to address these problems. NPSLE will likely develop among lupus patients in the first 5 years from SLE onset. The development and exact pathogenetic mechanisms of the disease also remain controversial but the discovery of the blood-brain barrier injury has given points of clarity. The focus of management is based on the identified etiology. Targets include symptomatic treatment and addressing the underlying SLE process. Likewise, the use of corticosteroids, cyclophosphamide, mycophenolate mofetil, azathioprine, antimalarial agents, warfarin or low dose aspirin depending on the pathways involved is also being utilized with positive results. More researches are being done to better elucidate the complex nature of NPSLE.

**Keywords:** systemic lupus erythematosus, neuropsychiatric lupus, NPSLE, autoantibody, autoimmunity

#### **1. Introduction**

Systemic lupus erythematosus is a complex autoimmune disease that affects virtually all organ systems. The interplay of the cellular make-up of the affected host and environment creates aberrancy that leads to a cascade of inflammatory response causing organ damage. The central and peripheral nervous system similar to other organs impaired by lupus exhibit more complicated manifestations. This in turn has resulted to a difficult timely recognition of the disease for an appropriate management. Within the past 10 years or more, researches worldwide are being done to address this problem. Neuropsychiatric systemic lupus erythematosus (NPSLE) had been described in several medical literatures These included the pathogenesis, mechanisms and current approach to management and treatment. Although still limited, more information is coming with the advancement of medical knowledge and technology regarding systemic lupus erythematosus and neuropsychiatric involvement.

#### **2. Pathogenesis**

The pathogenesis of NPSLE is being discussed in several literatures. There is no doubt that multiple pathogenic mechanisms are involved. Likewise, it encompasses a variety of process including cytokines, autoantibodies, and other infiltrating cells (cell-mediated inflammation).

The underlying mechanisms of neurologic manifestations depend on whether the central nervous system (CNS) or the peripheral nervous system (PNS) is being involved. For the CNS manifestations to occur, the primary injury can either be directed towards the vasculature or the brain parenchyma. The vascular injury includes damage to both large and small vessels via thromboembolic events, often as a consequence of antiphospholipid (aPL); a bland vasculopathy of small vessels characterized by vascular hyalinization, perivascular inflammation, and endothelial proliferation; and atherosclerotic lesions [1].

The disruption of BBB is central to the pathophysiology of NPSLE. This serves as the primary factor for the transit of pathogenic proteins towards the CNS. On the other hand, the BBB permeability remains debatable in diffuse NPSLE. Diamond et al. have provided data on studies from murine models supporting the role of circulating anti-DNA autoantibodies in the development of NPSLE thru cross-reactivity with the NR2 subunits of the anti-N-methyl-D-aspartate receptors during inflammation causing damage in the integrity of BBB [2, 3]. Other substances which are also associated with NPSLE include intrathecal IgG production, antiphospholipid (aPL) antibodies, antiribosomal P antibodies, anti-endothelial cell antibodies (AECAs), anti-microtubuleassociated protein 2 (MAP-2) antibodies, anti-aquaporin 4 antibodies (AQP4) and anti-suprabasin antibodies (**Table 1**). Meanwhile, intrathecal markers associated with NPSLE include matrix metalloproteinase-9 (MMP-9) and plasma activator inhibitor 1 (PAI-1). CSF levels of interleukin 6 (IL-6) and interleukin 8 (IL-8) are significantly correlated with MMP-9. Aside from BBB, other brain structures which are disrupted enhancing the penetration of the central nervous system (CNS) include the meningeal barrier, and the choroid plexus. Aseptic meningitis occurs as a result of a breached meningeal barrier in SLE patients and also with non-steroidal anti-inflammatory drug (NSAID) use. Similarly, due to immunosuppression, infectious meningitis is likely. Studies involving the choroid plexus have shown that in SLE patients, immune complex deposition is evident but nonspecific [4, 5].

The most recent studies have referred to the proposed two pathologic mechanisms contributing to the development of NPSLE, the autoimmune or inflammatory pathway and the ischemic or thrombotic pathway. The previous pathway includes autoantibodies, proinflammatory cytokines, chemokines, microglia and C1q while the latter involves the immune complexes, complement system and the aPL autoantibodies. Both of which manifest with focal and diffuse neuropsychiatric symptoms [6].

Intrathecal IgG production is found elevated during a central nervous system flare. The aPL antibodies are directly related to focal NPSLE via autoantibody-mediated thrombosis. This predisposes aPL-antibody positive patients for the increased risk of cerebrovascular events such as stroke and transient ischemic attack (TIA). Studies also shown that aPL antibodies hasten the process of atherosclerosis among susceptible individuals. The risk of developing NPSLE is twice as likely among those with aPL antibodies than those who are aPL-antibody negative individuals. Seizures, chorea, cognitive dysfunction and myelopathy were also observed among those with aPL antibodies. On the other hand, greater cognitive impairment manifests with persistently elevated anti-cardiolipin. This consistent finding is also similar among SLE patients


*PAI-1: plasma activator inhibitor; MMP-9: matrix metalloproteinase; aPL: antiphospholipid; AECAs: antiendothelial cell autoantibodies; anti-MAP2: anti-microtubule protein 2; anti-AQP4: anti-aquaporin 4; anti-NMDAR/ NR2: glutamate receptor antibodies; and IL: interleukins.*

#### **Table 1.**

*Antibodies/proteins of interest implicated in NPSLE.*

with positive lupus anticoagulant. The ischemic events are implicated in the brain regions including the amygdala, frontal cortex and hippocampus. The anti-ribosomal P antibodies have not been associated in coexisting cognitive impairment. These antibodies have an association with NPSLE, particularly psychosis, but are not reliable to make a diagnosis. These are highly specific for SLE and found to be present in up to 46% of patients with SLE. Other NPSLE syndromes including seizure, coma, depression, aseptic meningitis and transverse myelopathy are also associated with these antibodies. MAP-2, a cellular protein, is strictly found in neurons and essential to the cytoskeletal integrity. In one study, involving 100 SLE patients and 74 patients with various neurologic disorders, it was found out that more SLE patients as compared to neurologic disease control patients have presence of anti-MAP-2 antibodies (17% vs. 4%, p = 0.028) AQP4 is a water channel protein expressed on astrocytic foot processes around blood vessels controlling the flow of water into and out of the brain. In one study, anti-AQP4 antibodies were detected in 3% of all patients with NPSLE and 27% of patients with NPSLE who had demyelinating lesions. Suprabasin is a protein used as an epidermal differentiation marker. In one study it was found out that titers of anti-suprabasin antibodies were higher in the patients with NPSLE than patients with non-neuropsychiatric SLE, multiple sclerosis and normal-pressure hydrocephalus. MMP-9 enhances T cell migration through connective tissue. It is secreted by cells found in the walls of the vasculature including macrophages, T lymphocytes, endothelial cells, and smooth muscle. Intrathecal levels of MMP-9 in significant amount are found in all patients with SLE as compared to non-SLE patients including those with NPSLE. Similarly, intrathecal levels of PAI-1 have been found to be significantly elevated in patients with NPSLE [1, 4, 5].

AECAs play a role in the pathogenesis of NPSLE. It recognizes molecules bound to endothelial cells, antigens expressed constitutively or cytokine-induced and adhesion molecules. Psychosis and depression are also implicated with AECAs due to vasculitis

via expression of adhesion molecules, cytotoxic effect, induction of apoptosis and the activation of coagulation cascade [7].

Previous studies have revealed the associations of elevated CSF IL-6 levels with seizures and IFN-α with lupus psychosis. Some evidence suggested the roles of other cytokines including IL-2, IL-8 and IL-10. Another interesting study involves microglial cells. They play a fundamental role in regulating BBB function and in shaping brain circuits and development ('synaptic pruning') [8].

#### **3. Clinical manifestations**

The American College of Rheumatology (ACR) subcommittee categorized NPSLE into 19 distinct syndromes encompassing the CNS and PNS. CNS manifestations include acute confusional state, psychosis, headache, and mood disorders for the diffuse processes (**Table 2**). On the other hand, seizures, myelopathy and chorea are the CNS focal manifestations [1].

In a meta-analysis of 5057 SLE patients, it was found out that NPSLE prevalence varied from 17.6 to 44.5% in retrospective and prospective studies [8]. NPSLE may be the first manifestation of the disease. CNS syndromes are more common than peripheral [9]. The most frequent NPSLE manifestations are headaches, depression, anxiety and cognitive dysfunction. In one study, ethnicity and older age are factors associated with earlier neuropsychiatric damage [10].

Headaches manifest in more than 50% of SLE patients with both migrainous and tension-type headaches being described [1]. Headache in SLE is not associated with disease activity, treatment, imaging such as MRI and biomarkers including aPL, anti-P, and glutamate receptor antibodies (anti-NR2) or any specific antibody. Seizures occur in about 10 to 20% of SLE patients and associated with increased morbidity and mortality. Generalized tonic-clonic seizure is the most common type. In contrast to headache, seizure tend to be associated with APS, disease activity, severe organ damage and other NPSLE manifestations. It is crucial to rule out other causes of seizures such as infections [9, 10].

Cognitive dysfunction which manifests with deficits in memory, thinking and concentration is increasingly observed among SLE patients. Studies suggested the association of aPL, anti-NMDAR/anti-NR2 antibodies, and anti-Sm antibodies [1, 9].

Psychosis, depression and anxiety can occur in SLE. Postal et al. found that mood disorders were associated with disease activity, high prednisone doses, cutaneous disease, and longitudinal extensive transverse myelitis [11]. Depression is the most common disorder in NPSLE, and its lifetime prevalence may reach 65% [12]. Higher incidence of depression among SLE patients were associated with anti-P and anti-NMDA receptor autoantibodies [9]. Interestingly, anti-P antibody levels were 5- to 30-fold higher during the active phase of SLE psychosis, but not during other SLE manifestations [13]. Also, it is very important to consider the differential diagnoses of psychosis in SLE patients such as CNS infection, primary schizophrenia, metabolic abnormalities and psychosis secondary to glucocorticoid therapy or illicit drugs [1]. Anxiety disorders are common and found in up to 40% of SLE patients [14].

SLE patients are susceptible to developing cerebrovascular events such as ischemic stroke and intracerebral hemorrhage with the previous more common than the latter. The development of cerebrovascular disease in SLE patients can be attributed to accelerated atherosclerosis and inflammatory mediators such as cytokines, aPL antibodies and complement system [1, 9]. In relation to which, one systematic review


#### **Table 2.**

*American college of rheumatology classification of neuropsychiatric syndromes in systemic lupus erythematosus.*

found a fivefold increase in the risk of ischemic stroke in patients with aPL antibodies compared to controls [15]. Posterior reversible encephalopathy syndrome (PRES) is a known mimic of CNS lupus. It is characterized by headache, seizures, altered consciousness, and visual changes often in a background of hypertension, eclampsia, renal disease and/or immunosuppressive therapies [1].

Chorea is the most common movement disorder observed among SLE patients. It appears in 2–3% of adult patients more common in women. Recent evidence suggests an autoimmune mechanism related to aPL antibodies. Aseptic meningitis is also a manifestation of SLE. It can occur at any time during the disease course presenting with headache and/or altered mental status. Other causes include infections of various etiologies (bacterial, viral, fungal or tuberculosis), immunosuppressants or medications and malignancy [9, 10].

Optic neuropathy and myelopathy rarely occur as part of the spectrum of NPSLE. The manifestations of optic neuropathy include monocular central visual loss, color vision and afferent pupillary problems. It can be caused by thrombotic or inflammatory mechanisms in the setting of lupus. On the other hand, myelopathy is a syndrome affecting the spinal cord presenting with numbness, paresthesia of bilateral lower extremity and weakness that can progress to involve the upper limbs. A characteristic symptom of which is a band-like pain or discomfort around the abdomen [1]. Lupus myelitis occurs in about 1.5% of cases. In nearly half of the patients with SLE, acute transverse myelitis occurs as the first clinical manifestation within the first 5 years of diagnosis. Histopathology findings revealed ischemic or thrombotic myelopathy or a localized inflammation [9]. Several studies link transverse myelitis-SLE with aPL antibodies [16].

Demyelination in NPSLE is also seen in about 0.3% of cases. It can be an isolated syndrome but can overlap with multiple sclerosis [17]. SLE patients also present with peripheral neuropathy. One study had demonstrated a 6% prevalence of peripheral neuropathy, 67% of which were attributable to SLE. Sensorimotor axonal polyneuropathy was the most common type. Similarly, it is crucial to rule out other causes of

peripheral neuropathy such as diabetes mellitus, hypothyroidism,, infections, vitamin deficiency, malignancy and drugs [1].
